Targeted molecular dynamics of an open-state KcsA channel

Compoint, Mylène; Picaud, Fabien; Ramseyer, Christophe; Giŗardet, C.

doi:10.1063/1.1869413

Cited by 35 publications

(39 citation statements)

References 38 publications

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“…Previously, TMD has been successfully applied to study conformational transitions of KcsA channel, chymotrypsin, and other proteins (27,45,46). However, to our knowledge, analysis of CCK2R activation represents the first successful application of TMD to a GPCR.…”

Section: Discussionmentioning

confidence: 99%

“…However, these data could not answer the questions of how, at a molecular level, the changes involving movements of helices and amino acids actually proceed, in which order they occur, and how they are coordinated. To answer these questions, TMD, an in silico method that can simulate intricate conformational changes in proteins as the pathway between two conformations, was applied to CCK2R (27).…”

Section: Modeled Structure Of Active Cck2r (Cck2r*)-becausementioning

confidence: 99%

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Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor

Marco

Foucaud

Langer

et al. 2007

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) represent a major focus in functional genomics programs and drug development research, but their important potential as drug targets contrasts with the still limited data available concerning their activation mechanism. Here, we investigated the activation mechanism of the cholecystokinin-2 receptor (CCK2R). The three-dimensional structure of inactive CCK2R was homology-modeled on the basis of crystal coordinates of inactive rhodopsin. Starting from the inactive CCK2R modeled structure, active CCK2R (namely cholecystokinin-occupied CCK2R) was modeled by means of steered molecular dynamics in a lipid bilayer and by using available data from other GPCRs, including rhodopsin. By comparing the modeled structures of the inactive and active CCK2R, we identified changes in the relative position of helices and networks of interacting residues, which were expected to stabilize either the active or inactive states of CCK2R. Using targeted molecular dynamics simulations capable of converting CCK2R from the inactive to the active state, we delineated structural changes at the atomic level. The activation mechanism involved significant movements of helices VI and V, a slight movement of helices IV and VII, and changes in the position of critical residues within or near the binding site. The mutation of key amino acids yielded inactive or constitutively active CCK2R mutants, supporting this proposed mechanism. Such progress in the refinement of the CCK2R binding site structure and in knowledge of CCK2R activation mechanisms will enable target-based optimization of nonpeptide ligands.

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Section: Discussionmentioning

confidence: 99%

Section: Modeled Structure Of Active Cck2r (Cck2r*)-becausementioning

confidence: 99%

Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor

Marco

Foucaud

Langer

et al. 2007

Journal of Biological Chemistry

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“…The conformational aspects of the gating mechanism have been studied mainly through the use of MD simulations (see references [31][32][33][34] for examples), albeit a recent work has addressed the same process from an electronic point of view by means of QM calculations. [35] Here, the point is to understand how the lowest part of the channel cavity (the bundle formed by the four N-terminal fragments of helices S5 and the four Cterminal fragments of helices S6) can switch from a structure that does not allow the passage of K + ions (because of the restricted volume of the gate) to one that allows it, and vice versa.…”

Section: Ions Permeation and Selectivitymentioning

confidence: 99%

Modeling hERG and its Interactions with Drugs: Recent Advances in Light of Current Potassium Channel Simulations

2008

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The hERG K(+) channel is responsible for the rapid delayed rectifier current in cardiac myocytes, and a block of its functioning may be related with the (inherited or drug-induced) long QT syndrome. For this reason, in recent times, some interest has arisen around computational studies aimed at developing hERG/drug models for the prediction of drug binding (docking) modes, in view of the assessment of the hERG blocking potential. On the other hand, voltage-gated K(+) channels have been the subject of molecular simulations for several years, and rigorous protocols for studying the main aspects of their functions (permeation, gating, voltage sensing) have been published. In this article, we briefly introduce these classical computational works on K(+) channels, and then review in depth the reports on the latest advanced modeling studies on hERG. The aim is to put the hERG modeling work in the more general context of the ion channel simulations field, to show the peculiarity of hERG on the one side, and also to indicate some possible new avenues in the use of modeling techniques to increase our knowledge of this important channel.

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“…Several X-ray structures of these molecular arrangements have been published [2][3][4][5][6][7], leading to considerable progress in our understanding of this phenomenon. Subsequent to the determination of these structures, multiple molecular dynamics simulations have been performed [8][9][10][11][12][13][14][15][16][17][18][19][20], yielding some information on how the selectivity could be operating. It is now clear that there is a narrow pore that acts as the selectivity filter and it is well conserved in all reported structures [7].…”

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confidence: 99%